1. Field of the Invention
This invention disclosed is referring to the preparation of novel phenylalkylcarbohydroxamic acids substituted in the phenyl nucleus and to the use thereof in a pharmaceutical formulation; and relates to the field of hydroxamic acids employed for the inhibition of blood platelet aggregation.
2. Description of the Prior Art
Certain substituted phenylalkylcarbohydroxamic acids are known to those skilled in the art. Biologically active phenylmethylcarbohydroxamic acids possessing at least a substituent in the para-position ("p" position) are known from Belgian Pat. Nos. 648,892 and 661,226. Substituted phenylvinylcarbohydroxamic acids have furthermore been described in the Belgian Pat. No. 701,983. From the numerous publications with respect to these known hydroxamic acid derivatives which have appeared in the literature, such as 211 NATURE 752 (1966), 18 ARZNEIMITTELFORSCHUNG 1404 (1968), and J. MED. CHEM. 13, 211 (1970), it is obvious that a predominant characteristic of these compounds is a pronounced anti-inflammatory activity, with possible side-effects in the CNS field, such as a sedative action. Studies of the structure-activity relationships have inter alia shown that the anti-inflammatory activity is restricted to the hydroxamic acids derived from substituted phenylacetic acid derivatives and to a less extent from cinnamic acid derivatives. It is emphatically stated in 13 J. MED. CHEM. 211 (1970) that hydroxamic acids derived from substituted phenylpropionic acid derivatives no longer show any anti-inflammatory activity. Hence, a need arose in the art to (1) abolish the anti-inflammatory activity of such hydroxamic substituted acids; (2) not to retain sedative properties; (3) not to intensify CNS activity; while (4) trying to utilize any blood platelet aggregative inhibition properties.
Also it may be noted in 18 ARZNEIMITTELFORSCHUNG 1404 (1968) that removal or blockage of the hydroxylamine function (of the hydroxamic acid concerned) also causes to a great extent the anti-inflammatory activity to disappear. This statement is more or less confirmed by (1) the U.S. Pat. No. 3,190,800, which teaches that ethers of a large group of hydroxamic acids (including phenylalkylcarbohydroxamic acids) are depressives, and by (2) the French Pat. No. 1,332,352, which teaches that lower alkyl ethers of the hydroxamic acid derived from 3,4,5-tri-alkoxy-substituted cinnamic acid are sedatives.
On the basis of the above information, a conclusion that conversion to an ether group of the known hydroxamic acids (derived from substituted phenylacetic acid and substituted cinnamic acid) abolishes the anti-inflammatory activity, but considerably intensifies CNS activity, would be justified to one skilled in the art.
Additional patents of interest are U.S. Pat. Nos. 3,890,377 and 3,972,934 to Winston S. Marshall. Both U.S. Pat. Nos. 3,972,934 and 3,890,377 disclose selected 3-phenoxy-phenylalkyl amines (and the amides, alcohols, tetrazoles and carbamates related thereto) useful as anti-inflammatory agents with favourable analgesic and anti-pyretic side effects. Buu Hoi in U.S. Pat. No. 3,479,396 teaches the manufacture of a group of substituted arylaceto hydroxamic acids prepared by reacting hydroxylamine and alkyl acetate, in which the meta-position is optionally substituted. This U.S. patent corresponds to the two Belgium patents cited above. Finally, Nordman in U.S. Pat. No. 3,383,407 teaches the manufacture of 3,4,5-trimethoxybenzohydroxamic acids having sedative properties.
Surprisingly, it has now been found that hydroxamic acids derived from at least meta-substituted phenylpropionic acid and phenylbutyric acid derivatives exert a pronounced inhibition of blood platelet aggregation, while they also accelerate considerably the disaggregation of platelet aggregates already formed.